1. Field of the Invention
The present invention relates to the delivery of antimicrobial functions or agents from the surface of coatings, particularly the release of antimicrobial functions or agents from the surface of medical devices, especially medical devices that have been inserted or implanted into patients. The invention particularly relates to the controlled or controllable delivery of such functions or agents.
2. Background of the Art
It has become common to treat a variety of medical conditions by introducing or implanting a temporary or permanent medical device partly or completely into a patient. These devices may be inserted or implanted (the term “implanted” shall be used herein to reflect both short term insertion and long term implantation) into many different organs and glands such as the heart, brain, esophagus, stomach, trachea, colon, biliary tract, urinary tract, vascular system or other location within a human or veterinary patient. These implants may be in the form of a device such as a pump, delivery system, sensing system, stent, catheter, balloon, wire guide, cannula, electrical pulsing or pacing system or the like. However, when such a device is introduced into and manipulated through the vascular system or implanted at a selected site, the tissue or vascular walls can be disturbed or injured. Clot formation or thrombosis, bacterial collection and infection and other adverse events can occur at the injured site or implantation site, causing acute or chronic injury or infection at the sire. Moreover, if the medical device is left within the patient for an extended period of time, thrombus and infections may often form on the device itself, again causing serious potential for damage and illness. As a result, the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, stroke, site infection, sepsis, implant rejection, and the like. Thus, the use of such a medical device can entail the risk of causing problems as serious or worse than the problems that the device's use was intended to ameliorate.
Another way in which blood vessels undergo stenosis is through disease. Probably the most common disease causing stenosis of blood vessels is atherosclerosis. Atherosclerosis is a condition which commonly affects the coronary arteries, the aorta, the iliofemoral arteries and the carotid arteries. Atherosclerotic plaques of lipids, fibroblasts, and fibrin proliferate and cause obstruction of an artery or arteries. As the obstruction increases, a critical level of stenosis is reached, to the point where the flow of blood past the obstruction is insufficient to meet the metabolic needs of the tissue distal to (downstream of) the obstruction. The result is ischemia.
Many medical devices and therapeutic methods are known for the treatment of atherosclerotic disease. One particularly useful therapy for certain atherosclerotic lesions is percutaneous transluminal angioplasty (PTA). During PTA, a balloon-tipped catheter is inserted in a patient's artery, the balloon being deflated. The tip of the catheter is advanced to the site of the atherosclerotic plaque to be dilated. The balloon is placed within or across the stenotic segment of the artery, and then inflated. Inflation of the balloon “cracks” the atherosclerotic plaque and expands the vessel, thereby relieving the stenosis, at least in part.
While PTA presently enjoys wide use, it suffers from two major problems. First, the blood vessel may suffer acute occlusion immediately after or within the initial hours after the dilation procedure. Such occlusion is referred to as “abrupt closure.” Abrupt closure occurs in perhaps five percent or so of the cases in which PTA is employed, and can result in myocardial infarction and death if blood flow is not restored promptly. The primary mechanisms of abrupt closures are believed to be elastic recoil, arterial dissection and/or thrombosis. It has been postulated that the delivery of an appropriate agent (such as an antithrombic) directly into the arterial wall at the time of angioplasty could reduce the incidence of thrombotic acute closure, but the results of attempts to do so have been mixed.
A second major problem encountered in PTA is the re-narrowing of an artery after an initially successful angioplasty. This re-narrowing is referred to as “restenosis” and typically occurs within the first six months after angioplasty. Restenosis is believed to arise through the proliferation and migration of cellular components from the arterial wall, as well as through geometric changes in the arterial wall referred to as “remodeling.” It has similarly been postulated that the delivery of appropriate agents directly into the arterial wall could interrupt the cellular and/or remodeling events leading to restenosis. However, like the attempts to prevent thrombotic acute closure, the results of attempts to prevent restenosis in this manner have been mixed.
Non-atherosclerotic vascular stenosis may also be treated by PTA. For example, Takayasu arteritis or neurofibromatosis may cause stenosis by fibrotic thickening of the arterial wall. Restenosis of these lesions occurs at a high rate following angioplasty, however, due to the fibrotic nature of the diseases. Medical therapies to treat or obviate them have been similarly disappointing.
A device such as an intravascular stent can be a useful adjunct to PTA, particularly in the case of either acute or threatened closure after angioplasty. The stent is placed in the dilated segment of the artery to mechanically prevent abrupt closure and restenosis. Unfortunately, even when the implantation of the stent is accompanied by aggressive and precise antiplatelet and anticoagulation therapy (typically by systemic administration), the incidence of thrombotic vessel closure or other thrombotic complication remains significant, and the prevention of restenosis is not as successful as desired. Furthermore, an undesirable side effect of the systemic antiplatelet and anticoagulation therapy is an increased incidence of bleeding complications, most often at the percutaneous entry site.
Other conditions and diseases are treatable with stents, catheters, cannulae, pacemakers, defibrilators, pumps, eluent drug delivery systems and other devices inserted into organs such as the heart, the brain, the esophagus, the trachea, the colon, biliary tract, urinary tract and other locations in the body, or with orthopedic devices, implants, or replacements. It would be desirable to develop devices and methods for reliably delivering suitable agents, drugs or bioactive materials directly into a body portion during or following a medical procedure, so as to treat or prevent such conditions and diseases, for example, to prevent site infection, either from short term insertion or long term implantation of the device. As a particular example, it would be desirable to have devices and methods which can deliver an antibacterial agent or other medication to the region of implantation, where the release of the antibacterial agent can be externally controlled, rather than relying on predetermination of a release rate. Additionally, the release rate should not be dependent upon external reading of the device or regular sampling of the blood stream to determine when release rates of a medical pump should be modified to adjust to altering patient conditions. The antibacterial delivery system should also be minimally additive in size or volume to the device being implanted. It would also be desirable that such devices would controllably deliver their agents over both the short term (that is, the initial hours and days after treatment) and the long term (the weeks and months after treatment). It would also be desirable to provide relatively precise control over the delivery rate for the agents, drugs or bioactive materials, and to limit invasive control in effecting that delivery. This would be particularly advantageous in therapies involving the delivery of a chemotherapeutic agent to a particular organ or site without requiring reinsertion or additional insertion to the patient through an intravenous catheter (which itself has the advantage of reducing the amount of agent needed for successful treatment). This would reduce the trauma to the patient and reduce additional invasion of the patient. A wide variety of therapies can be similarly improved by the practice of this methodology. Of course, it would also be desirable to avoid degradation of the agent, drug or bioactive material during its incorporation on or into any such device.
Problems experienced with the use of pumps, structural implants, pacemakers, defibrillators, and catheters, particularly catheters designed for urinary tract infections or indwelling vascular catheters such as those used in patients receiving long term chemotherapy for malignancies or antimicrobials for persistent infections present a significant risk in patients with an indwelling catheter. Although many such infections are asymptomatic, they are sometimes serious and can result in prolonging the length of stay and increasing the cost of hospital care. Bacteria are believed to gain access to the catheterized bladder either by migration from the collection bag and/or catheter or by ascending the periurethral space outside the catheter. It has been found that by coating catheters with silver or silver oxide reduced the incidence of catheter associated bacteriuria. Silver is known to possess antibacterial properties and is used topically either as a metal or as silver salts. It is not absorbed to any great extent and the main problem associated with the metal is argyria, a general gray discoloration. Although silver is an effective topical antibacterial agent, it tends to act only on bacteria in direct contact with the surface and is subject to chemical reactions such as oxidation, which reduce its long term effectiveness.
Additionally, where release of the antibacterial agent from a coating is solely by mass transfer release by elution or migration out of a coating, drug is unnecessarily released during movement to the implantation site. At a minimum, this drug is wasted during implantation, or in the case of highly active agents, it is released to a region where that drug is not needed.
U.S. Pat. No 5,418,130 describes a method for inactivating viral and/or bacterial contamination in blood cellular matter, such as erythrocytes and platelets, or protein fractions. The cells or protein fractions are mixed with chemical sensitizers and irradiated with, for example, WV, visible, gamma or X-ray radiation. In particular, quaternary ammonium or phosphonium substituted, halo-psoralen compounds are described as being useful. This system is for use on solutions or dispersions of cells or the like and is not described for application on medical devices.
A typical drug delivery system with a biodegradable release layer is shown by U.S. Pat. No. 6,342,250. U.S. Pat. No. 6,251,136 describes a method of forming a release catheter comprising a method for coating a stent, comprising the steps of: providing a stent; applying a base layer of sticky material to selected surfaces of said stent; applying pharmacological agent in micronized, dry form to selected surfaces coated by said base layer; and applying a membrane forming polymer coating through which said pharmacological agent is able to diffuse to all surfaces of said stent.
U.S. Pat. No. 4,723,950 by Lee relates to a microbicidal tube which may be incorporated into the outlet tube of a urine drainage bag. The microbicidal tube is manufactured from polymeric materials capable of absorbing and releasing anti-microbial substances in a controllable sustained time release mechanism, activated upon contact with droplets of urine, thereby preventing the retrograde migration of infectious organisms into the drainage bag. The microbicidal tube may be produced by one of three processes: (1) a porous material, such as polypropylene, is impregnated with at least one microbicidal agent, and then coated with a hydrophilic polymer which swells upon contact with urine, causing the leaching out of the microbicidal agent; (2) a porous material, such as high density polyethylene, is impregnated with a hydrophilic polymer and at least one microbicidal agent; and (3) a polymer, such as silicone, is compounded and co-extruded with at least one microbicidal agent, and then coated with a hydrophilic polymer. A broad range of microbicidal agents are disclosed, including chlorhexidine and triclosan, and combinations thereof. The purpose of Lee's device is to allow the leaching out of microbicidal agents into urine contained in the drainage bag; similar leaching of microbicidal agents into the bloodstream of a patient may be undesirable.
U.S. Pat. No. 6,168,601 shows a system utilizing the eutectic forming ability of related drugs to control release. Biologically active materials are provided in a cylindrical carrier medium with better control over the rate of delivery and length of time of delivery by providing a carrier having dissolved or dispersed therein at least two compounds having a common biologically active nucleus, but with different solubility parameters. The combination of the two different variants of the same drug with different solubility parameters provides the material with control over the rate of release of the compounds (by varying the proportions of the variants) and most importantly, extending the useful life of the device by enabling release of effective levels of the compounds over a longer period of time. The cylindrical carrier medium, comprised of silicone, further includes a tail, a skirt, or a rate-limiting membrane.
U.S. Pat. No. 5,091,442 by Milner relates to tubular articles, such as condoms and catheters, which are rendered antimicrobially effective by the incorporation of a non-ionic sparingly soluble antimicrobial agent, such as triclosan, The tubular articles are made of materials which include natural rubber, polyvinyl chloride and polyurethane. Antimicrobial agent may be distributed throughout the article, or in a coating thereon. A condom prepared from natural rubber latex containing 1% by weight of triclosan, then dipped in an aqueous solution of chlorhexidine, is disclosed. U.S. Pat. Nos. 5,180,605 and 5,261,421, both by Milner, relate to similar technology applied to gloves.
U.S. Pat. No. 6,224,579 discloses a method of producing a non-infecting medical article by imbuing the device in a solution containing synergistic amounts of two antibiotics. That article comprises a medical article prepared by exposing a polymer-containing medical article, for an effective period of time, to a treatment solution comprising between about 0.3 and 1.5 percent of a silver salt and between about 0.1 and 20 percent triclosan, where the treatment solution and the medical article do not contain chlorhexidine or a chlorhexidine salt.
Improved coatings and control of drug delivery is desired for medical devices.